Abstract
I have previously commented on the weak evidence supporting suggestions (by both Freemantle and Thase) that amitriptyline has dual action [1]. Gupta et al. now include mirtazapine (6-aza-mianserin) as a dual action drug. However, some evidence indicates mirtazapine is not significantly serotonergic in humans at any dose level and may not posses dual action.
If we compare mirtazapine and SSRIs we find three indices of serotonin elevation are all quite different: serotonergic effects at therapeutic dose; serotonin toxicity in overdose (characterized by clonus, hyperreflexia, tremor, agitation and diaphoresis); and serious serotonin toxicity when mixed with monoamine oxidase inhibitors [2]. All are absent with mirtazapine and common with SSRIs [3], [4]. Serotonergic drugs produce typical symptoms of serotonin toxicity in overdose; mirtazapine does not.
The spectrum concept of serotonin toxicity, or serotonin syndrome [2–5] assists our understanding of serotonin-related effects in these three clinical situations by clarifying that serotonin levels increase progressively as side effects merge into toxicity. This allows deductions concerning the in vivo potency of a drug's serotonergic effects because it suggests drugs like mirtazapine, that exhibit none of these three classes of serotonergic effects, may have no clinically relevant serotonergic action [6]. The same points are also equally relevant to trazodone and nefazodone, as well as mianserin and amitriptyline. It is unlikely that 5-HT2A receptor antagonism accounts for this since the serotonin reuptake inhibitor clomipramine, which is a potent 2A blocker, does produce all three above classes of serotonergic effects.
Gillman and Whyte have constructed a hierarchy for the probability of producing serotonin toxicity for a range of drugs and that may be used to infer their serotonergic potency, whatever their supposed mechanism of action. A detailed explanation and further references are in Gillman [7].
These differences also match trial data and clinical impressions of effect; for example, efficacy in obsessive compulsive disorder: mirtazapine none; SSRIs good. Also, neuro-endocrine probe data suggests neither mirtazapine, nor mianserin, elevate 5-HT1A-mediated neurotransmission, because they do not elevate prolactin [8], as do most serotonergic drugs.
It is fine irony that clomipramine, the original and perhaps most effective SNRI, has now been available in Australia for 20 years; however, it is doubtful that many doctors even appreciate that it is an SNRI. Marketing considerations and advertising's spin doctors influence the (mis)perception of drugs as dual action as much as knowledge of psychopharmacology: that may be held to reflect on the profession. It seems illogical, bizarre and sad that this interplay between marketing and bureaucracy (the TGA, etc.) means clomipramine is not permitted for depression via the Australian PBS. Doctors can be fined for using the first, cheapest (and still the best?) SNRI to treat depression. Is that evidence of a clever country?